Receptor mediated endocytosis is a process by which cells can internalize specific target molecules. First the molecules bind to the membrance receptors and then the membrane receptors bind to an adaptin protein called Adaptor Protein-2 which then binds to clathrin, activating the formation of a coated pit. The adaptins act as a sort of docking mechanism, catching and then keeping the receptors docked in the coated pit and unable to move around in the plasma membrane.The pit then forms a clathrin coated vesicle, and is eventually internalized, containing the bound receptor, and any substances enveloped in the extracellular fluid. Once internalized, the clathrin coated vesicle sheds its clathrin coat in order to fuse with other vesicles to form early endosomes. Endosomes typically maintain a lower pH and this lower pH causes the receptor proteins to shift their shapes and release their substrates, i.e. the target molecules. The receptors may then separate from the endosome and return to the cell membrane for reuse. The endosome could also either fuse with a lysosome for degredation or release of its contents, or release its contents on the other side of the cell via exocytosis in a process called transcytosis. (Formation and uncoating of a coated pit)
Receptor-mediated endocytosis.
Substances Internalized Through Receptor Mediated Endocytosis:
-Low-density lipoproteins (carrying cholesterol) (A picture showing a defective LDL receptor protein that does not bind to the adaptin protein and thus is not internalized contributing to higher extracellular cholesterol levels and thus promoting atherosclerosis and the other problems associated with serum cholesterol (the "bad" cholesterol))
Research: (Paclitaxel, a cancer fighting chemical that disrupts microtubule breakdown)
Shown above: ANG1005- Angiopep-2 and three molecules of paclitaxel
First Author: Reinhard Gabathuler
Title: ANG1005 (Paclitaxel-AngioPep Conjugate) for the Treatment of Brain Primary or Metastatic Tumors
Organisms: Rats
Organization: angiochem
Researchers have developed a molecule that utilizes receptor mediated endocytosis to bypass the very selective blood-brain barrier to treat brain cancer. The molecule binds to the Density Lipoprotein Receptor Related Protein-1 (LRP-1) and then crosses the blood-brain barrier.
"In contrast to free paclitaxel, which is normally prevented from reaching the brain by the P-glycoprotein efflux pump, ANG1005 is efficiently transported across the blood-brain barrier, with approximately 100-fold higher transport rate compared to free paclitaxel and 10-fold higher transport rate than temozolomide," .
The molecule ANG1005 has been shown to be as effective in treating cancer as free paclitaxel:
"The anti-tumour activity of paclitaxel was maintained with ANG1005 compared with free paclitaxel. There was no loss of activity." He also found a significant inhibition of brain tumour growth in rats when they were treated with ANG1005, whereas tumours in rats that were treated with paclitaxel did not have their growth inhibited. "This is probably because free paclitaxel is not able to enter the brain," http://www.angiochem.com/docs/posters/Poster_BBBD_Mar13-08.pdf http://www.sciencedaily.com/releases/2008/10/081022073724.htm
Receptor mediated endocytosis is a process by which cells can internalize specific target molecules. First the molecules bind to the membrance receptors and then the membrane receptors bind to an adaptin protein called Adaptor Protein-2 which then binds to clathrin, activating the formation of a coated pit. The adaptins act as a sort of docking mechanism, catching and then keeping the receptors docked in the coated pit and unable to move around in the plasma membrane.The pit then forms a clathrin coated vesicle, and is eventually internalized, containing the bound receptor, and any substances enveloped in the extracellular fluid. Once internalized, the clathrin coated vesicle sheds its clathrin coat in order to fuse with other vesicles to form early endosomes. Endosomes typically maintain a lower pH and this lower pH causes the receptor proteins to shift their shapes and release their substrates, i.e. the target molecules. The receptors may then separate from the endosome and return to the cell membrane for reuse. The endosome could also either fuse with a lysosome for degredation or release of its contents, or release its contents on the other side of the cell via exocytosis in a process called transcytosis.
Substances Internalized Through Receptor Mediated Endocytosis:
-Low-density lipoproteins (carrying cholesterol)
-Enzymes
-Insulin
-Some hormones
-Iron (through transferrin)
Research:
Shown above: ANG1005- Angiopep-2 and three molecules of paclitaxel
First Author: Reinhard Gabathuler
Title: ANG1005 (Paclitaxel-AngioPep Conjugate) for the Treatment of Brain Primary or Metastatic Tumors
Organisms: Rats
Organization: angiochem
Researchers have developed a molecule that utilizes receptor mediated endocytosis to bypass the very selective blood-brain barrier to treat brain cancer. The molecule binds to the Density Lipoprotein Receptor Related Protein-1 (LRP-1) and then crosses the blood-brain barrier.
"In contrast to free paclitaxel, which is normally prevented from reaching the brain by the P-glycoprotein efflux pump, ANG1005 is efficiently transported across the blood-brain barrier, with approximately 100-fold higher transport rate compared to free paclitaxel and 10-fold higher transport rate than temozolomide," .
The molecule ANG1005 has been shown to be as effective in treating cancer as free paclitaxel:
"The anti-tumour activity of paclitaxel was maintained with ANG1005 compared with free paclitaxel. There was no loss of activity." He also found a significant inhibition of brain tumour growth in rats when they were treated with ANG1005, whereas tumours in rats that were treated with paclitaxel did not have their growth inhibited. "This is probably because free paclitaxel is not able to enter the brain,"
http://www.angiochem.com/docs/posters/Poster_BBBD_Mar13-08.pdf
http://www.sciencedaily.com/releases/2008/10/081022073724.htm
Link to a guided Animation on the Internalization of LDL:
"Tutorial 5.3 Receptor-Mediated Endocytosis." 20 October 2008. <http://bcs.whfreeman.com/thelifewire/content/chp05/0502003.html>.
Research Links:
"Crossing Blood-Brain Barrier: Scientists Develop Drug Delivery System For Brain Cancers, Other." 22 October 2008. <http://www.sciencedaily.com/releases/2008/10/081022073724.htm>.
Gabathuler, Reinhard, Michel Demuele. "ANG1005 (Paclitaxel-AngioPep Conjugate) for the Treatment of Brain Primary or Metastatic Tumors." AngioChem. 20 October 2008. <http://www.angiochem.com/docs/posters/Poster_BBBD_Mar13-08.pdf>.
Other Resources Used:
"Intracellular Compartments: Exocytosis, Endocytosis, and the Lysosome." 20 October 2008. <http://courses.bio.psu.edu/fall2005/biol230weve/tutorials/tutorial6.htm>.
"Low-density lipoprotein." Wikipedia. Wikimedia Foundation, Inc. 20 October 2008. <http://en.wikipedia.org/wiki/LDL>.
Marieb, Elaine N. Human Anatomy & Physiology. San Francisco: Pearson Benjamin Cummings, 2004. 79-81.
"Paclitaxel." Wikipedia. Wikimedia Foundation, Inc. 20 October 2008. <http://en.wikipedia.org/wiki/Taxol>.
Spurger, Linda. "Receptor Mediated Endocytosis." 2002. The University of Texas Medical Branch. 20 October 2008. <http://cellbio.utmb.edu/CELLBIO/recend.htm#clathrin>.
"The pathway of receptor mediated endocytosis." 20 October 2008. <http://srs.dl.ac.uk/VUV/home-page/hot-topics/endo.html>.